Annotation

Journal of Medical Genetics (1971). 8, 37.

Phenylketonuria
Though phenylketonuria (PKU) is a rare con- fancy or by the screening of sibs of known cases.
dition, it is one of the few causes of mental retarda- With the introduction of screening on blood samples,
tion for which medical treatment is available. There the net has been widened further.
are, however, those who doubt this statement, claim- Phenylalanine is an essential amino acid. It is
ing that the evidence for it is not proven and sug- mainly metabolized to tyrosine but catabolism also
gesting that actual harm may be done by a low occurs to phenylpyruvic acid and subsequent con-
phenylalanine diet (Bessman, 1966; Birch and version to other metabolites. Carpenter, Auerbach,
Tizard, 1967). and DiGeorge (1968) have discussed five enzymes
Much of the confusion has arisen, firstly, from a which may be involved in the production of hyper-
failure to realize that hyperphenylalaninaemia can phenylalaninaemia. These include phenylalanine
arise in a variety of ways and PKU of the type de- hydroxylase, dihydropteridine reductase, phenyl-
tected by Phenistix is only one of these. Secondly, alanine transaminase, tyrosine transaminase, and
the quality of the dietary and biochemical care has p-hydroxyphenylpyruvic acid oxidase. The in-
not been uniformly good, and, thirdly, the diet has hibiting effect of raised metabolites on one or more
been stated at a variety of ages, often when marked of these enzymatic mechanisms must also be con-
brain damage has already occurred. sidered.
During the past few years it has become apparent In PKU of the kind recognized for a number of
that the Phenistix test on urine for the detection of years now, there was a rapid rise in phenylalanine
classical PKU is unsatisfactory. In October 1968 levels in the blood to high values, increased meta-
the Medical Research Council Working Party on bolites in the urine, and the development of severe
Phenylketonuria reviewed some mass screening mental retardation. In a few such patients direct
procedures and considered that the Guthrie test on measurement of phenylalanine hydroxylase activity
blood (Guthrie, 1961) would be a suitable procedure in the liver has shown a deficiency (Justice, O'Flynn,
though it was hoped that its introduction would not and Hsia, 1967). Before the development of any
be a deterrent to the continued use and further study dietary treatment almost all cases of PKU must have
of other screening tests. As a result of this report been of this type (classical PKU).
the Department of Health and Social Security However, from screening techniques dependent
recommended in HM (69) 72 that Phenistix testing on the detection of phenylalanine in blood, patients
of infants should be replaced by the Guthrie test on have been discovered with smaller increases in
blood. Since the Phenistix test does not become phenylalanine than seen in classical PKU. One
positive until significant quantities of phenyl- group may be considered to have atypical PKU;
alanine metabolites are present in urine, the method during the neonatal period the plasma phenyl-
only detected those children who had high phenyl- alanine level rises more slowly and levels off below
alanine levels in the blood and large quantities of 30 mg./100 inl. Metabolites such as phenylpyruvic
metabolites in the urine. With the introduction of acid are present in smaller amounts, and these
screening tests which detect raised levels of phenyl- children can tolerate larger amounts of phenyl-
alanine in blood (this includes the Guthrie test), alanine in their diet than those with classical PKU
greater numbers of children give a positive result (Carpenter et al., 1968). Loading such patients
and diagnosis has become increasingly complex. with phenylalanine does not differentiate
Historically, the way in which PKU has been from those with classical PKU, and few directthem esti-
diagnosed has therefore undergone marked changes. mations of liver enzymes have been performed.
Originally patients were found by screening popula- Whether or not children of this type should really be
tions of retarded patients in mental institutions. treated with a low phenylalanine diet is not really
Later, some patients were still found in this way, but known. In a further group of patients the phenyl-
others were found by routine urine testing in in- alanine level lies between 5 and 20 mg./100 ml.
37
 38 Barbara E. Clayton
plasma. There is no absolutely reliable evidence
on which to base a decision as to whether diet
should or should not be used, but probably this
clinical situation is harmless (Carpenter et al., 1968).
High levels of phenylalanine may occur without
excess phenylpyruvic acid in the urine. These
findings are associated with a high intake of protein
and are corrected when the intake is reduced. It is
thought that the condition arises from an abnor-
mality in the phenylalanine transaminating system
(Auerbach, DiGeorge, and Carpenter, 1967).
Occasionally an infant is born with delayed matura-
tion of the enzymes necessary for the catabolism of
phenylalanine. Such an infant presents all the
biochemical features of PKU but on treatment he
requires increasing amounts of phenylalanine to
maintain a normal level in the blood. Such patients
eventually grow out of the condition completely
(Moncrieff and Wilkinson, 1961; Stephenson and
McBean, 1967).
About a quarter of infants of low birthweight and
some full-term ones show raised tyrosine levels of up
to 20 mg./100 ml. plasma (British Medical Journal,
1968). It is quite usual to find associated raised
levels of phenylalanine up to about 15 mg./100 ml.
It is thought that the raised tyrosine or parahydroxy-
phenylpyruvic acid inhibits the phenylalanine
hydroxylating system.
The cause of mental retardation in PKU is far
from understood. There is incomplete myelina-
tion of the central nervous system (e.g. Malamud,
1966), and Menkes (1968) has suggested that there
may be decreased synthesis of myelin. Certainly,
animal experiments indicate that high doses of
phenylalanine early in life can cause marked
changes in the composition of the brain (Agrawal,
Bone, and Davison, 1969; Chase and O'Brien,
1970). In addition, phenylalanine and its meta-
bolites inhibit the transport and concentration of
other amino acids in liver and brain, and they inter-
fere with the activity of enzymes involved in the
metabolism of amino acids (Neame, 1961; Tashian,
1961).
In the dietary treatment, the aim has been to
maintain the plasma phenylalanine levels at or
slightly above the normal range. In the diet
natural protein is largely replaced by artificial pre-
parations low in phenylalanine. These are generally
commercial preparations containing protein hydro-
lysate, and they have an unpleasant taste and are
often bulky. Their actual phenylalanine content
varies according to the preparation used, and with
some of them it can be difficult to lower the plasma
phenylalanine level and yet provide sufficient
nitrogen intake. Recently a pure amino acid mix-
ture instead of a hydrolysate has been used with
considerable success (Bentovim et al., 1970); it
allowed the inclusion in the diet of greater amounts
of phenylalanine-free foods, and was more palatable
and readily accepted. As a result food problems
were greatly reduced.
The treatment given to children with PKU has
been of a variable standard. The diet is un-
doubtedly difficult, particularly since phenylala-
nine is an essential amino acid. Extremely
worrying side effects have been observed including
anaemia (Royston and Parry, 1962), retardation of
growth (Fisch, Gravem, and Feinberg, 1966),
severe protein deficiency (Pitt, 1967), and even death
(Dodge et al., 1959). There is evidence too that
early infantile undernutrition can be detrimental to
intellectual development (Davison and Dobbing,
1966). The use of the diet is, however, compatible
with healthy physical growth, and the fact that in
some children treatment has been poor is no reason
for condemning it.
Where the care of a child with PKU has been
good from the early weeks of life adequate intel-
lectual development takes place (Clayton, Moncrieff,
and Roberts, 1967; Baumeister, 1967; Fuller and
Shuman, 1969; Hudson, Mordaunt, and Leahy,
1970). Though the mean intelligence quotient of
these early treated patients tends to lie about 10
points below that of the normal population, they
are educable at normal schools and differ strikingly
from most untreated or late-treated PKU children
whose mean intelligence quotient is about 50.
For good results these children should be treated
in centres where there is a team comprising not
only the paediatrician but a dietitian, biochemist,
psychiatrist, and psychologist. In this way the
staff gain experience in caring for these children,
laboratory facilities can be geared to their needs,
and proper dietary supervision can be provided.
Where a dietitian looks after numbers of these
children she can provide the recipes and domestic
'know-how' so essential for the mothers. How to
bake a low phenylalanine birthday cake is just as
important as accurate phenylalanine levels or
clinical care! In my experience the single PKU
patient at a hospital does not in general get this type
of care, and it is in this situation that disastrous
effects of poor diet are liable to occur.
It is already known that the offspring of phenyl-
ketonuric mothers not on diet show a variety of
abnormalities including defective growth, convul-
sions, microcephaly, and congenital heart defects.
The literature on this has been reviewed recently
(Yu and O'Halloran, 1970), and no less than 65 of 68
offspring were mentally retarded. These children
 Phenylketonuria
did not have PKU but had been damaged in utero by
circulating metabolites. In due course treated
PKU mothers of normal intelligence will become
pregnant, and this poses a new problem. The
reintroduction of a low phenylalanine diet during
pregnancy is essential but presents considerable
difficulties. It is unpalatable and, since there is
much that is poorly understood about dietary re-
strictions in pregnancy and amino acids are actively
transported across the placenta, severe maternal
dietary restrictions may be necessary. In addition,
the diet should presumably be introduced before
conception. Information is sparse, though Allan
and Brown (1968) have described the successful use
of diet in one pregnant subject. A number of
treated patients are now in their teens. Some
thought must be given to the way their care will be
organized since the staff of maternity units have
neither the experience nor facilities for providing
the total care for such women. Since women of
child-bearing age at present have not been screened
for hyperphenylalaninaemia, the investigation of
non-specific mental retardation in a child should
include examination of the plasma amino acids of
the mother.
Paediatricians with considerable experience of
treating these children are generally in no doubt that
intellectual deterioration can be prevented, pro-
vided the diet is begun early. Their experience is
such that it would be unethical to conduct a ran-
domized clinical trial of diet at this late stage. It
may be that some hyperphenylalaninaemias are be-
ing treated unnecessary, but with more accurate
diagnostic criteria this may be avoided in the future.
Two problems face the paediatrician particularly at
this stage: what plasma phenylalanine level should
he try to maintain with diet and when can the diet
be stopped ?
In the light of past experience it is to be hoped
that trials will be organized for metabolic disorders
other than PKU now being recognized more fre-
quently as a result of new screening procedures. In
histidinaemia for example no less than half the sub-
jects with the biochemical stigmata are mentally
normal. In addition, within one family apparently
identical biochemical findings may be associated
with normal intellect in one sib and severe mental
subnormality in another. The indiscriminate use
of diet in every infant with a raised level of histidine
in the plasma is therefore to be deprecated, and it is
difficult to see how the problem can be solved
with either a randomized clinical trial or very careful
follow-up of untreated infants.
In spite of all the difficulties, the results for well-
treated PKU patients in Britain are most encourag-
39
ing. With increasing knowledge and awareness
of the problems still posed, the future looks hopeful.
BARBARA E. CLAYTON,
The Hospital for Sick Children,
Great Ormond Street,
London W.C.1.
REFERENCES
Agrawal, H. C., Bone, A. H., and Davison, A. N. (1969). Inhibition
of brain protein synthesis by phenylalanine. Biochemical journal,
112, 27P.
Allan, J. D. and Brown, J. K. (1968). Maternal phenylketonuria
and foetal brain damage. An attempt at prevention by dietary
control. In Some Recent Advances in Inborn Errors of Meta-
bolism, p. 14. Ed. by K. S. Holt and V. P. Coffey. Livingstone,
Edinburgh.
Auerbach, V. H., DiGeorge, A. M., and Carpenter, G. G. (1967).
Variations in hyperphenylalanmemia. In Amino Acid Metabolism
and Genetic Variation, p. 11. Ed. by W. L. Nyhan. McGraw-Hill,
New York.
Baumeister, A. A. (1967). The effects of dietary control on intelli-
gence in phenylketonuria. AmericanJournal of Mental Deficiency,
71, 840-847.
Bentovim, A., Clayton, B. E., Francis, D. E. M., Shephard, J., and
Wolff, 0. H. (1970). Use of an amino acid mixture in treatment of
phenylketonuria. Archives of Disease in Childhood, 45, 640-650.
Bessman, S. P. (1966). Legislation and advances in medical know-
ledge-acceleration or inhibition ? journal of Pediatrics, 69, 334-
338.
Birch, H. G. and Tizard, J. (1967). The dietary treatment of
phenylketonuria: not proven ? Developmental Medicine and Child
Neurology, 9, 9-12.
British Medical Journal (1968). Disorders of tyrosone metabolism.
(Leading article.) 3, 511-512.
Carpenter, G. G., Auerbach, V. H., and DiGeorge, A. M. (1968),
Phenylalaninemia. Pediatric Clinics of North America, 15, 313-
323.
Chase, H. P. and O'Brien, D. (1970). Effect of excess phenylalanine
and of other amino acids on brain development in the infant rat.
Pediatric Research, 4, 96-102.
Clayton, B., Moncrieff, A., and Roberts, G. E. (1967). Dietetic
treatment of phenylketonuria: a follow-up study. British Medical
Journal, 3, 133-136.
Davison, A. N. and Dobbing, J. (1966). Myelination as a vulnerable
period in brain dev elopment. British Medical Bulletin, 22,40-44.
Department of Health and Social Security (1969). Screening for
early detection of phenylketonuria. (H.M. (69) 72). London.
Dodge, P. R., Mancall, E. L., Crawford, J. D., Knapp, J., and Paine,
R. S. (1959). Hypoglycemia complicating treatment of phenyl-
ketonuria with a phenylalanine-deficient diet. New England
journal of Medicine, 260, 1104-1111.
Fisch, R. O., Gravem, H. J., and Feinberg, S. B. (1966). Growth
and bone characteristics of phenylketonurics. American journal
of Diseases of Children, 112, 3-10.
Fuller, R. N. and Shuman, J. B. (1969). Phenylketonuria and intelli-
gence: trimodal response to dietary treatment. Nature (London),
221, 639-642.
Guthrie, R. (1961). Blood screening for phenylketonuria. journal
of the American Medical Association, 178, 863.
Hudson, F. P., Mordaunt, V. L., and Leahy, I. (1970). Evaluation
of treatment begun in first three months of life in 184 cases of
phenylketonuria. Archives of Disease in Childhood, 45, 5-12.
Justice, P., O'Flynn, M. E., and Hsia, D. Y. Y. (1967). Phenyl-
alanine-hydroxylase activity in hyperphenylalaninaemia. Lancet,
1, 928-929.
Malamud,N. (1966). Neuropathologyofphenylketonuria. Journal
of Neuropathology and Experimental Neurology, 25, 254-268.
Medical Research Council Working Party on Phenylketonutia (1968).
Present status of different mass screening procedures for phenyl-
ketonuria. British MedicalJournal, 4, 7-13.
Menkes, J. H. (1968). Cerebral proteolipids in phenylketonuria.
Neurology, 18, 1003-1008.
40 Barbara E. Clayton
Moncrieff, A. and Wilkinson, R. H. (1961). Further experiences in
the treatment of phenylketonuria. British Medical Journal, 1,
763-767.
Neame, K. D. (1961). Phenylalanine as inhibitor of transport of
amino-acids in brain. Nature (London), 192, 173-174.
Pitt, D. (1967). Phenylalanine maintenance in phenylketonuria.
Australian PaediatricJournal, 3, 161-163.
Royston, N. J. W. and Parry, T. E. (1962). Megaloblastic anaemia
complicating dietary treatment of phenylketonuria in infancy.
Archives of Disease in Childhood, 37, 430-435.
Stephenson, J. B. P. and McBean, M. S. (1967). Diagnosis of
phenylketonuria (phenylalanine hydroxylase deficiency, tem-
porary and permanent). British Medical_Journal, 3, 579-581.
Tashian, R. E. (1961). Inhibition of brain glutamic acid decar-
boxylase by phenylalanine, valine, and leucine derivatives: a
suggestion concerning the etiology of the neurological defect in
phenylketonuria and branched-chain ketonuria. Metabolism, 10,
393-402.
Yu, J. S. and O'Halloran, M. T. (1970). Children of mothers with
phenylketonuria. Lancet, 1, 210-212.

Corrigendum
Annotation: Genetics of Immunity Deficiency, Syn-
dromes, by Kay, December 1970, Vol. 7, p. 310, in the
section discussing IgA deficiency, column 2, lines 29-31
should read
... the anology of fetal haemoglobulin formation in
trisomy-D (Patau's syndrome). However in trisomy-E
(Edwards' syndrome) immunological abnormalities have
not been . . .